Peanut allergy is one of the most common food allergies; most children develop this allergy early in life, do not outgrow it and are at risk for severe and life-ending anaphylactic reactions. There is a critical need for a proactive treatment for peanut allergy and we along with others are developing specific types of immunotherapy that will cause these patients to be no longer allergic to peanuts. The significance of this proposal is based on our landmark studies that have examined the effects of peanut sublingual immunotherapy (SLIT) showing a substantial increase in the amount of peanut that a peanut allergic patient can ingest while on therapy and in some cases causing long-term clinical tolerance when the therapy is discontinued. SLIT involves the administration of small amounts (micrograms to milligrams) of allergen extract under the tongue. It offers a novel means of treatment for food allergy and seems well suited for several reasons, including the superior safety of this approach. In this proposal, we will build on the preliminary data generated by our previous work showing that SLIT is feasible and safe but variably efficacious in older peanut-allergic children. The long-term goal of this proposal is the development of a treatment for peanut allergy that will lessen the likelihood of an accidental allergic reaction to peanuts in thee patients. With the following Aims designed to understand the mechanism of this treatment, this project will answer the research question: In newly diagnosed peanut-allergic children between the ages of 12 and 48 months, does 36 months of maintenance treatment with 4 milligrams per day of peanut SLIT induce functional tolerance, when compared to placebo? Specific Aim 1: Determine the mechanisms by which SLIT induces hyporesponsiveness in basophils and mast cells (MCs) in peanut allergic subjects on peanut SLIT. Specific Aim 2: Determine the peanut allergen-specific CD4+ T cell frequencies and phenotypes, as well as the suppressive function of Treg cells that are associated with the development of clinical tolerance to peanuts. Specific Aim 3: Determine the effect of peanut-specific mucosal and systemic humoral immune responses in SLIT on clinical tolerance. These studies will help us identify the mechanism and durability of the desensitized state and then the subsequent development of tolerance to foods after SLIT. A treatment for peanut allergy is critically needed the completion of these studies wil provide a strong scientific basis for the development of SLIT and other types of therapy that hope to produce long-term clinical tolerance to peanuts and other foods. -